Devices and methods for nebulizing fluids for inhalation

ABSTRACT

A nebulizer comprising an aerosol generator and a titration mechanism comprising a dosing mechanism, a screw assembly, a plunger and an actuator, wherein the dosing mechanism is rotatably mounted in the nebulizer and the plunger is mounted in the nebulizer to travel along a longitudinal axis substantially perpendicular to the plane of rotation of the dosing mechanism. The actuator is mounted to the nebulizer to travel in the direction of the longitudinal axis. The screw mechanism allows the rotation of the dosing mechanism to fix a variable distance of travel of the plunger based on the selected dose, without moving the plunger longitudinally. This allows the user to verify and if necessary correct the selected dose prior to any drug being released from the vial. Operation of the actuator causes longitudinal movement, through the screw mechanism, to the plunger. The actuator always moves a fixed distance along the longitudinal axis, while the plunger always moves a variable distance depending on rotation of the dosing mechanism to a selected dose.

CROSS-REFERENCES TO RELATED APPLICATIONS

[0001] This application is a continuation-in-part and claims thepriority of benefit of U.S. Provisional Application Serial No.60/346,789 filed on Jan. 7, 2002 the complete disclosure of which ishereby incorporated herein by reference and this application is acontinuation-in-part and claims the priority of benefit of U.S.Provisional Application Serial No. 60/403,454, filed Aug. 13, 2002 thecomplete disclosure of which is hereby incorporated herein by reference

BACKGROUND OF THE INVENTION

[0002] The present invention is directed to the field of methods anddevices for nebulizing fluids. In particular, the present invention isdirected to methods and devices by which a user may select a dose ofmedication from a multi-dose vial and nebulize the selected dose forinhalation.

BRIEF SUMMARY OF THE INVENTION

[0003] The present invention provides a nebulizing device that ispreferably a hand-held nebulizing device for inhalation of the nebulizedfluid. The device has a nebulizing element and a mouthpiece throughwhich the user inhales the nebulized fluid. The nebulizing element,which may interchangeably be referred to as an aerosolization element,may be a vibrating element with holes through which the fluid is ejectedas a mist, although other suitable nebulizing elements may be usedwithout departing from the present invention.

[0004] The fluid is held in a container that holds a number of doses ofthe fluid. The container delivers the fluid to a reservoir. A plungeracts on the container to cause fluid to flow from the container into thereservoir. A screw mechanism controls the distance of travel of theplunger. A dosing mechanism allows a user to select a particular dose tobe administered by inhalation, and the dosing mechanism cooperates withthe screw mechanism to set a distance of travel of the plunger thatcorresponds to the dose selected by the user. The dosing mechanism mayrotate within a plane. An actuation mechanism is operated by the user tocarry out the actual movement of the plunger according to the distanceof travel set by the dosing mechanism. In this manner, a user can verifythe amount of fluid selected for aerosolization before that amount offluid is moved into the reservoir for aerosolization. If a user seesthat the dose amount needs to be modified, the user can do so by furtheroperation of the dosing mechanism before any fluid is actually releasedfrom the container. In this manner, an inadvertent selection of a dosewill not result in loss of that amount of fluid, because the user hasthe opportunity to verify and if called for readjust the selectionbefore fluid is moved from the container into the reservoir.

[0005] The actuator will typically travel in a direction perpendicularto the plane of rotation of the dosing mechanism. In this manner, dosingcan be done easily and accurately by the user with a simple rotationaction prior to attempting to deliver the dosed amount into a reservoirfor aerosolization. The actuation can be done simply, in a discretemanner, prior to or while the user has oriented the device forinhalation through the mouthpiece of the device. In addition, theactuation mechanism is configured so that a single, predeterminedmovement of the actuation mechanism causes the plunger to travel theentire distance that a user selects, regardless of the particulardistance of travel chosen by the user. Thus, delivery of the fluid fromthe container to the reservoir for aerosolization may be carried out bya single motion by the user operating the actuation mechanism, thusreducing encumbering maneuvering that could be required in delivering aparticular amount of fluid from the container to the reservoir. Thiscontributes to ease of operation of the nebulizer, and thus improves thelevel of care that a user may administer in using the nebulizer. In somecases, a patient may not comply with a particular drug regimen becauseit is perceived as inconvenient or embarrassing, as might be the casewith injunctions or cumbersome inhalation devices. Accordingly, thepresent invention minimizes such potential non-compliance factorsbecause the user may dial a dose out of the line of sight of others, theuser may operate the actuator with a simple button press, and the userneeds only a single hand to bring the nebulizer to the mouth.

BRIEF DESCRIPTION OF THE DRAWINGS

[0006] Embodiments of the invention will be described in greater detailbelow with reference to the drawings.

[0007]FIG. 1 is schematic representation of a partial exploded side viewof a nebulizer embodiment according to the present invention.

[0008]FIG. 2 is a perspective view of the nebulizer of FIG. 1.

[0009]FIG. 3 is a flow chart showing a method and steps in accordancewith the present invention.

[0010]FIG. 4 is a cutaway cross-sectional view of the device as depictedin FIG. 2 and in accordance with the present invention.

[0011]FIG. 5A is a detail cross-section of the nebulizer of FIGS. 1 and2.

[0012]FIG. 5B is a detail cross-section of the nebulizer of FIGS. 1 and2.

[0013]FIG. 6. is a detail cross-sectional cutaway view of the nebulizerof FIGS. 1 and 2.

[0014]FIGS. 7A and 7B are detail cross-sectional cutaway views of thenebulizer depicted in FIGS. 1 and 2.

DETAILED DESCRIPTION OF THE INVENTION

[0015] Referring to FIG. 1, a nebulizing inhaler according to thepresent invention is represented schematically. The device 10 comprisesa titration mechanism 20, a vial mechanism 22, a reservoir 90 and anaerosol generator 100. The titration mechanism comprises a titrationcontrol mechanism, which may be referred to a dosing mechanism 30, ascrew mechanism 50, a plunger 60 and an actuator 40. The plunger isconfigured to travel to and fro, as explained in further detail below,in the direction of arrow 62 (this being the “to” motion, the “fro”motion being the reverse thereof). Accordingly, and as depicted in FIG.1, arrow 62 defines the axis of travel of the plunger 60. The actuatoris configured to travel to and fro, as explained in further detailbelow, in the direction of the arrow 42 (this being the “to” motion, the“fro” motion being the reverse thereof). Accordingly, and as depicted inFIG. 1, the arrow 42 defines the longitudinal axis of travel of theactuator 40. The axis of travel of the actuator 40 is also representedas the broken line A in FIG. 2.

[0016] The vial mechanism 22 comprises a container, such as a vial 23that defines a central longitudinal axis 24 and movable seal 70 movablycaptured in the vial 23. The moveable seal 70 is movable along thecentral axis 24 of the vial 23 by action of plunger 60 upon the moveableseal 70 in the direction of arrow 62. A liquid 80 is provided in thevial mechanism 22. The liquid 80 is moved into a reservoir 90 by actionof the movable seal 70 against the liquid 80, as the moveable seal ismoved, in the direction of arrow 62, by action of the plunger in thedirection of arrow 62, upon the moveable seal 70. Once the liquid is inthe reservoir 90, the liquid 80 can be nebulized for inhalation by auser.

[0017] Upon exhaustion of liquid from the vial, the vial may be removedand replaced as necessary with a new vial containing liquid, thusputting the nebulizer in a state ready for operation. The vial 23 may beof a transparent material, such as glass, and thus the level of fluid 80within it can readily be seen. The level of fluid in the vial 23 can beseen through window 25 in the device 10 (see FIG. 2).

[0018] Liquid in the reservoir may be nebulized by an aerosolizationelement 100 (FIG. 1). The aerosolization element may comprise a firstface 102 that faces into the reservoir and a second face 104 that isdirected to a mouthpiece. The aerosolization element may have aplurality of apertures 106 extending through from the first face 102 tothe second face 104 (see FIGS. 5A and 5B). Liquid on the reservoir sideof the aerosolization element may be drawn through the apertures andemitted, as an aerosolized mist 110, from the other. For example, theliquid may be drawn through the apertures by vibratory motion of theelement. The apertures of the element may be tapered. The taper may havea wider portion 107 toward the reservoir and narrower portion 108 awayfrom the reservoir and toward the mouthpiece (FIG. 5B). Theaerosolization element may be non-planar, and may be concave. Theconcave side may be positioned toward the reservoir 90. The sideemitting the aerosolized mist 100 may be convex. Other configurations ofmoving fluid from the reservoir through the aerosolization element andemitting the fluid as a mist therefrom may be employed without departingfrom the present invention.

[0019] When a new vial assembly is needed, the device 10 may be openedby operation of latch assembly 27, thus allowing removal of a spent vialassembly or vial and replacement thereof. The reservoir 90 may also beremoved and replaced by opening the device 10 by operation of latchassembly 27. The vial assembly 22 may be linked to the reservoir 90 insuch a manner that one cannot be removed from the other without breakageto one or both of these components. The vial assembly may have a collarwith one or more tabs, and the reservoir may have one or more detentsthat can interlock with the tabs. In this manner, the tabs and detentsmay hold the vial assembly and the reservoir together and prevent theirdisassembly from each other. With the vial assembly and the reservoirbeing assembled in such a manner, inadvertent use of the vial forpurposes other than use with the nebulizer, such as injection, can beavoided, as the concentration of drug within the liquid may be fargreater for inhalation than the concentration of the same drug in aliquid for injection. In this manner, both the vial assembly and thereservoir may need to be removed and replaced as a tandem assembly. Thepresent invention is embodied in the nebulizer described herein withoutone or both of the vial assembly and the reservoir, as these subassemblycomponents are likely to be removed and reassembled to each other andback into the nebulizer. Removable vial assemblies and removablereservoirs are described in co-assigned and co-pending applicationSerial No. 10/043,075 which is hereby incorporated herein in itsentirety. The present invention is also embodied in the nebulizerdescribed herein comprising the vial assembly and the reservoir, as wellas in methods of nebulizing liquid comprising providing a vial assemblyand a reservoir. The present invention is also embodied in methods ofnebulizing liquid comprising inserting the vial assembly in to anebulizer and comprising inserting a reservoir into a nebulizer.

[0020] The vial mechanism 22 may be received within the device 10 toalign with the titration mechanism such that the direction of travel ofthe actuator 40, the direction of travel of the plunger 60 and thedirection of travel of the movable seal 70 in the vial 23 are allsubstantially parallel. The vial mechanism 22 may be received within thedevice 10 to align with the titration mechanism in a substantiallycoaxial manner, such that the action of the actuator 40, the plunger 60and the movable seal 70 in the vial 23 are all substantially coaxial.Thus, when the vial mechanism 22 is placed within the device 10 thecentral axis 24 of the vial 23, and thus the axis of movement of themovable seal 70, which is captured within the vial 23, the axis oftravel of the plunger 60, and the axis of travel of the actuator 40 maybe substantially parallel and may be coaxial (see FIGS. 1, 2 and 4). Thedosing mechanism 30 defines an axis of rotation, and this axis may beand preferably is coaxial with the longitudinal axis of the vial 23 whenthe vial mechanism is placed in the nebulizer. Accordingly, the axis ofrotation of the dosing mechanism, the longitudinal axis of the vial andthe axis of travel of the plunger are all coaxial. An object of thepresent invention is a nebulizer of an overall longitudinal dimension(substantially parallel to the longitudinal axis of the vial) that willessentially fit in the hand of a user and be used substantiallyinconspicuously to increase user compliance with a chosen administrationregimen (FIG. 2). Similarly, an object of the present invention is anebulizer that can fit easily in a garment pocket or a small bag. Inorder to fit a sufficient quantity of fluid in the vial, for example, aweek's supply of insulin, while maintaining these size dimensionconsiderations and accommodating the reservoir, mouthpiece and othercomponents of the nebulizer, the present invention, in one embodiment,resides in a nebulizer having a vial of unconventional dimension withrespect to vials typically used in injection devices. Accordingly, inone embodiment, the nebulizer of the present invention has a vialassembly with a vial having a ratio of the internal diameter D, in theportion where the movable seal can travel, to the overall length L1 ofthe vial (FIG. 7A), for example, in the range of about 1:3.5 to about1:4.5, or between about 1:3.7 to about 1:4.2. Similarly, the ratio maybe between about 1:3.8 to about 1:4.0. The ratio may be about 1:3.9 Forexample, the vial may have a diameter of about 12 mm and a length ofabout 47 mm. Likewise, the vial may have a diameter of about 12.0 mm anda length of about 46.8 mm. Alternatively, the measurement of vial lengthcan be taken as the length of the effective volume of the vial L₂ (FIG.7A), the effective volume including only the portion of the vial inwhich moveable seal can occupy (as opposed to the narrowing neck), andthus the ratio of vial diameter to length of the effective volume may bebetween about 1:3.0 and abut 1:3.8, or between about 1:3.2 to about1:3.6, or between 1:3.3 to about 1:3.5, or about 1:3.4. For example,this length may be about 38 mm, or this length maybe about 37.7 mm.

[0021] In operation, a user operates the dosing mechanism 30 to select aparticular dose amount that the user desires to have nebulized forinhalation. The dosing mechanism acts upon the screw mechanism 50. Thescrew mechanism 50 is linked to the plunger 60. The actuator 40 islinked to the screw mechanism 50 so that linear movement of the actuator40 in the direction of arrow 42 causes linear movement of the plunger 60in the direction of arrow 62.

[0022] There is, however, no actual movement of the plunger 60 againstthe moveable seal by operation of the dose mechanism 30; rather,operation of the dose control 30 only sets the distance that the plungerwill be able to travel in the subsequent stroke of the actuator 40.Thus, if a user in advertently selects an incorrect dose, the user mayreadjust the dosing mechanism 30 for the desired amount of drug withoutwasting the previous incorrectly selected dose amount. In this manner,the user may select a dose to be nebulized, and after verificationcorrect this dose if that is necessary, before nebulization begins. Oncethe user has determined and selected the correct dose amount byoperation of dosing mechanism 30, the user presses the actuator 40 inthe direction of arrow 42. The pressing action of the actuator 40 actsupon the screw mechanism 50, which then moves the plunger 60 in thedirection of arrow 62. The distance that the plunger 60 travels, in thedirection of arrow 62, is controlled by the screw mechanism 50 accordingto the selected dose amount based on the user's operation of the dosingmechanism 30. In this manner, when the user is ready to commenceinhalation, after discreetly selecting a dose, the user may bring thedevice to the user's mouth and at this point press the actuator 40 witha single button press motion to deliver medication to the reservoir fornebulization. Alternatively, the user may select the dose and operatethe actuator to deliver the dose into the reservoir prior to raising thenebulizer to the user's mouth. Discreet dosing and delivery is animportant feature of the present invention, because it increases usercompliance with a prescribed regimen. Certain drugs, such as insulin,require administration during the course of a day, perhaps inconjunction with meals; thus a user may be forced to take a dose in apublic setting. In some cases, a user will not comply with a drugregimen because it is perceived as inconvenient or embarrassing.Accordingly, the present invention minimizes such potentialnon-compliance factors—the user may dial a dose out of the line of sightof others, the user may operate the actuator with a simple button press,and the user needs only a single hand to bring the nebulizer to themouth.

[0023] Accordingly, the actuator 40 is configured to travel a fixeddistance X (see FIGS. 1 and 2) and the screw mechanism 50 permits theplunger 60 to travel a variable distance Y (see FIG. 1), based on thedose amount selected by operation of the dosing mechanism 30. Thespecific distances of travel for the plunger 60 according to doseamounts selected by operation of the dosing mechanism 30 may bedetermined based upon interior diameter of the vial 23.

[0024] Screw mechanisms such as screw mechanism 50, that selectivelycontrol the linear distance a plunger may travel, based on a selectedsetting of a dosing mechanism, with such travel being carried out by auser moving an actuator a fixed distance, are known, for example, ininjection pens used by diabetics to selectively inject a chosen amountof insulin. Such injection pens are widely available, for example, fromDisetronic Medical Systems, AG, Burgdorf, Switerland. Such pens and aredescribed in the art, as for example, U.S. Pat. Nos. 4,883,472;5,730,629; 6,090,080; 6,106,501; 6,280,421 and 5,954,699, the entirecontents of which are hereby incorporated herein by reference.

[0025] When the plunger travels a variable distance Y according the doseamount selected by a user in first operating the dosing mechanism 30 andthen operating the actuator 40, it acts upon the movable seal 70. Themovable seal 70 moves within the vial 23 to displace an amount of liquid80 from the vial 23 into the reservoir 90. The reservoir 90 is in fluidcommunication with an aerosol generator 100, so that liquid displacedfrom the vial 23 into the reservoir 90, upon operation of the aerosolgenerator 100, is emitted from the device as fine droplets that form amist 110.

[0026] With reference to FIG. 2 the device 10 comprises a housing 12.The dosing mechanism 30 is rotatably attached to the housing 12. Thedosing mechanism rotates circularly in a plane as shown by arrow 35(FIGS. 1 and 2). Rotation of the dosing mechanism 30 causes operation ofthe screw assembly (see FIG. 1). An indicator 32 displays selectabledose amounts based on rotation of the dosing mechanism 30 by a user, sothat a user may select a displayed dose amount by rotating the dosingmechanism 30. Once a user has determined that the selected dose amountis correct, the user presses actuator 40 in the direction of arrow 42.The to and fro (i.e. forward and reverse) directions of travel of theactuator 40 may be substantially perpendicular to the plane of rotationof the dosing mechanism 30 (see FIGS. 1 and 2). The motion of theactuator 40 in the direction of the arrow 42 moves the selected doseamount of medication into the reservoir (see FIG. 1), so that operationof the aerosol generator 100 causes the fluid to be ejected from thedevice as a mist 110 (see FIG. 1).

[0027] Referring now to FIG. 3, a flow chart of steps according to thepresent invention is shown. Step 200 is the selection of a dose byoperation of a dose mechanism. Step 210 is the operation of a screwmechanism, based on the selection of the dose mechanism, to set adistance of travel of a plunger. Step 220 is the operation of anactuator to move the plunger according to the distance set by the screwmechanism. Step 230 is the displacement of fluid, by action of theplunger moving the set distance, from a vial into a reservoir. Step 240is the operation of an aerosol generator that is in fluid communicationwith the reservoir. Step 250 is the aerosolization of the fluid.

[0028] Referring again to FIG. 2, the window 25 may be covered with atransparent pane 26. The window 25, and thus the transparent pane 26,may have a curvature for better viewing of the vial 23 which may besubstantially cylindrical. The indicator 32 comprising a displayed dose34 so that a user may see the dose selected prior to pushing theactuator 40. The dosing mechanism 30 has a circular motion as shown byarrow 35. The circular motion of the dosing mechanism, as shown by arrow35, is substantially perpendicular to the axis of travel of the actuator40.

[0029] Referring to FIG. 4, a reservoir 90 receives the liquid that isdisplaced from the vial 23 upon actuation of the plunger 60. The liquidmay travel from the vial 23 to the reservoir 90 through a cannula 91.The reservoir may have a channel such as a delivery tube 92 and a lumen94, which lumen may be defined by a wall 95. The liquid may flow fromthe vial 23 through the cannula 91 and then through the delivery tube 92into the lumen 94. The reservoir is in fluid communication with anaerosolizing element 100 as described above. The first face 102 of theaerosolizing element 100 may be contiguous with the reservoir, so thatfluid in the reservoir will abut the first face of the aerosolizingelement. In this manner, a wide range of dosages of liquid may be placedwithin the reservoir by the user carrying out the single actuationmotion; for example, the dose moved into the reservoir may be 30microliters or, alternatively, for example, the dose moved into thereservoir may be 250 microliters. By placing the entirety of the liquidto be aerosolized in the reservoir at once, uninterrupted aerosolizationmay be carried out smoothly, without inconsistencies that might occur ifliquid were to be provided to the aerosolization element other than as asingle bolus, such as, for example, by a drop-by-drop delivery, or ifother modes of aerosolization are used, such as ultrasonic or jetnebulizers, both of which apply energy or force directly to the liquid.By creating aerosol from the liquid by vibration of an aperturedaerosolization element, less potential degradation of the drug and fargreater aerosol particle size control can be achieved, and likewisebetter dose accuracy can be achieved. The second face of theaerosolization element is positioned such that aerosol emanating from itmay be drawn through a mouthpiece 120 of the nebulizer 10. The fluid isdelivered into the reservoir in such a manner that the liquid may alsobe in contact with the first face 102 of the aerosolization element 100while in the reservoir.

[0030] The aerosolization element may be constructed of a variety ofmaterials, comprising metals, which may be electroformed to createapertures as the element is formed, as described, for example, in U.S.Pat. No. 6,235,177 assigned to the present assignee and incorporated byreference herein in its entirety. Palladium is believed to be ofparticular usefulness in producing an electroformed, multi-aperturedaerosolization element, as well as in operation thereof to aerosolizeliquids. Other metals that can be used are palladium alloys, such asPdNi, with, for example, 80 percent palladium and 20% nickel. Othermetals and materials may be used without departing from the presentinvention. The aerosolization element may be configured to have acurvature, as in a dome shape, which may be spherical, parabolic or anyother curvature. The aerosolization element may have a curvature overits majority, and this may be concentric with the center of theaerosolization element, thus leaving a portion of the aerosolizationelement as a substantially planar peripheral ring. The aerosolizationelement may be mounted on an aerosol actuator 112 having an aperturetherethrough, and this may be done in such a manner that the curved ordomed portion of the aerosolization element extends through the apertureof the aerosol actuator and the substantially planar peripheral ring ofthe aerosolization element abuts a face of the aerosol actuator. Theface of the aerosol actuator 112 closest to the first face of theaerosolization element may similarly be referred to, by convention, asthe first face 114 of the aerosol actuator. The face of the aerosolactuator 112 closest to the second face of the aerosolization elementmay likewise by convention be referred to as the second face 115 of theaerosol actuator. The aerosolization element may be affixed to theaerosol actuator 112 with by its substantially peripheral ring portionbeing mounted to the first face 114 of the aerosol actuator 112, withthe dome of the aerosolization element extending through the aperture ofthe aerosol actuator toward the second face of the aerosol actuator andmay extend beyond the second face of the aerosol actuator 112.

[0031] The aerosolization element may be vibrated in such a manner as todraw liquid through the apertures 106 of the aerosolization element 100from the first face to the second face, where the liquid is expelledfrom the apertures as a nebulized mist. The aerosolization element maybe vibrated by a vibratory element 130, which may be a piezoelectricelement. The vibratory element may be mounted to the aerosol actuator,such that vibration of the vibratory element may be mechanicallytransferred through the aerosol actuator to the aerosolization element.The vibratory element may be annular, and may surround the aperture ofthe aerosol actuator, for example, in a coaxial arrangement. A circuitrymay provide power from a power source, such as an internal battery,which may be rechargeable. A switch may be operable to vibrate thevibratory element and thus the aerosolization element, andaerosolization performed in this manner may be achieved withinmilliseconds of operation of the switch. Further, this manner ofaerosolization provides full aerosolization with a substantially uniformparticle size of mist being produced effectively instantaneously withoperation of the switch. The switch may be operable by a pressuretransducer, which may be positioned in the mouthpiece of the nebulizer.The pressure transducer may be in electrical communication with thecircuitry, and a microprocessor may also be in electrical communicationwith the circuitry, and the microprocessor may interpret electricalsignals from the pressure transducer, and may also operate the switch tobegin aerosolization. In this manner, nebulization can beginsubstantially instantaneously with the inhalation of a user upon themouthpiece. An example of such a sensor switch can be found inco-assigned and co-pending U.S. application Ser. No. 09/705,063 assignedto the present assignee, the entire content of which is herebyincorporated herein by reference.

[0032] Another transducer may be used to sense the absence or presenceof liquid in the reservoir, by sensing, for example, a differencebetween vibration characteristics of the aerosolization element, suchas, for example, differences in frequency or amplitude, between wetvibration and substantially dry vibration. In this manner, thecircuitry, may, for example by way of the microprocessor, turn thevibration off when there is essentially no more liquid to aerosolize,i.e., when the end of the dose has been achieved, thus minimizingoperation of the aerosolization element in a dry state. Likewise, theswitch may prevent vibration prior to delivery of a subsequent dose intothe reservoir. An example of such a switch is shown in co-assigned andco-pending U.S. application Ser. No. 09/805,498, the entire content ofwhich is hereby incorporated herein by reference.

[0033] The microprocessor may also have a timing capability, such thatonce aerosolization begins, it proceeds for a predetermined time, afterwhich aerosolization stops. In this manner, a particular regimen ofbreathing and aerosolization may be carried out. For example, a user maybe instructed to inhale for five seconds while the timing is set toaerosolize for only the first four seconds of such a breath maneuver.This timing may be predetermined based on a particular drug and aparticular target of the drug, such as, for example, the deep lung,which may be the target of administration for a systemic drug, such asinsulin.

[0034] The circuitry may also operate visual signals to a user, such asthe illumination of a light, a blinking of a light, or the illuminationor blinking of one or more of a plurality of lights. Further, aplurality of lights in a plurality of colors may be used. For example, alight may be illuminated to inform the user that the main power to thedevice is on, such that once a breath is taken, the breath switch willoperate the aerosolization element. Another light signal may inform theuser that the selected dose has been received in the reservoir, thusinforming the user that the nebulizer is ready for the user to take abreath through the mouthpiece. A light signal may also inform the userthat aerosol delivery has stopped based on a predetermined time foraerosolization, and, likewise, a light signal may inform the user when apredetermined regimen time for inhalation has elapsed, whereupon theuser may stop inhalation of a breath. Similarly, a light signal mayinform the user that the end of dose has been reached, as, for example,described above, and that the aerosolization is no longer taking place.Such a signal light may conveniently be a different color than othersignal lights. Accordingly, a user may be informed from this informationthat the user has completed inhaling the chosen dose, and additionalinhalation is not needed.

[0035] The screw mechanism 50 may comprise an internally threaded nut,which can be moved rotationally but not longitudinally. The threaded nutmay mate with an externally threaded rod, which may be the rod portion61 of the plunger 60, which can be moved longitudinally but notrotationally. Thus, rotation of the nut may move the rod longitudinally.Rotation of the actuator may be linked to cause rotation of the nut,thus advancing the rod and plunger. The rotation of the actuator may becalibrated to correspond to a predetermined longitudinal distance thatcorresponds to a volume of liquid displaced by movement of the plungeragainst the vial by that longitudinal distance. The plunger, however,may be maintained at a fixed distance from the stopper, so thatadvancing the plunger by rotation of the actuator does not immediatelyresult in the displacement of liquid from the vial. After the userdetermines that the correct dosage has been chosen, for example byobserving the visual display showing the dose that will be displacedinto the reservoir for aerosolization if actuation is carried out, theactuator is moved longitudinally the fixed distance X. Movement ofactuator causes longitudinal movement of the nut, which in turn carriesthe rod longitudinal a distance of X. The plunger is moved the distanceY which corresponds to X+D. Because D will vary from dose to dose, thedistance Y of the longitudinal travel of the plunger will also vary.

[0036] One example of such a scheme is illustrated in FIG. 6. As shown,the dosing mechanism 30 extends into the housing and has a centralopening into which the plunger 60 is housed. The dosing mechanism 30 isrotatable about the actuator 40, and when the actuator 40 is depressed,the dosing mechanism 30 moves axially into the device housing. Coupledto the dosing mechanism 30 is a threaded nut 31 that is threadablyconnected to plunger 60 (that also has mating threads about its shaft).The plunger 60 also includes an elongate detent (not shown) that isaxially slidable within a groove formed in a stop 32 that is fixed tothe device housing. In this way, the plunger 60 may move axially throughstop 32, but not rotationally. Further, a spring 33 is positionedbetween the nut 31 and the stop 32 to bias actuator in the homeposition.

[0037] In operation, the user rotates the dosing mechanism 30 to set thedesired dose. In so doing, the nut 31 also rotates. However, sinceplunger the 60 is prevented from rotating due to the stop 32, it movesaxially downward toward the vial, thus reducing the distance betweenplunger 60 and the vial. When the desired dose is set, the user pushesdown on the actuator 40. In turn, the dosing mechanism 30 and the nut 31are also axially moved downward. In so doing, the plunger 60 is moveddown the same distance. The plunger 60 will therefore engage the vialand dispense the appropriate dose. The travel of the plunger 60 isstopped when the nut 31 hits the stop 32. The actuator 40 may then bereleased to return to the initial position.

[0038] Such screw mechanisms are known to those skilled in the art, andare described, for example, in U.S. Pat. Nos. 4,883,472; 5,370,629; and5,954,699 previously incorporated herein by reference.

[0039] Over the course of a user dispensing the contents of a vial,which may contain, for example, a one week supply of a drug, such asinsulin, the plunger may have incrementally moved from its initialposition near the actuator to a final position abutting the plungerwhich has been moved essentially to the forward-most portion of the vial(see FIGS. 7A and 7B). The plunger must return to its initial positionto act upon a new vial. The screw mechanism 50 may have a release thatpermits the plunger to travel back to its original position. The releasemay have a lock to prevent inadvertent return of the plunger prior toexhaustion of a vial. An example of such a release and lock isdescribed, for example, in U.S. Pat. No. 5,954,699 previouslyincorporated herein.

[0040] Various alternative configurations to control the linear distanceof travel of the plunger by rotation of a dosing mechanism may beemployed without departing from the scope of the present invention. Forexample, rotation of the dosing mechanism may not cause longitudinalmovement of the plunger, but instead such rotation of the dosingmechanism may cause a threaded member to move longitudinally to controlthe longitudinal distance the plunger may travel on actuation.Alternatively, rotation of the dosing mechanism may cause threadedmembers to cooperate with each other to lengthen or shorten the distanceof longitudinal travel of the plunger or the screw mechanism, which maycarry the plunger in longitudinal travel with a stroke of the actuator.

[0041] It should be appreciated that, the present invention may bepracticed with alternative embodiments and with a variety of devices andmethods. Accordingly, it should be appreciated that the foregoing isdescriptive of the present invention and that certain changes ormodifications may be made without departing from the scope of thepresent invention.

What is claimed is:
 1. A nebulizer comprising: a medicine vial assembly containing a medicine fluid; a reservoir assembly that engages the medicine vial assembly in fluid communication therewith; an aerosol generator mounted in fluid communication with the reservoir assembly; and a titration mechanism comprising: a plunger situated to act upon the medicine vial assembly, a screw assembly mechanically engaged with the plunger, a titration control mechanism mechanically engaged with the screw assembly, and an actuator button situated to act upon the screw assembly to cause linear movement of the plunger; wherein operation of the titration control mechanism selectively sets the linear distance the plunger will be caused to move when the actuator button is pressed, wherein movement of the plunger causes the plunger to act upon the vial assembly in such a manner so as to displace fluid from the vial assembly into the reservoir assembly, and wherein the fluid in the reservoir assembly can be ejected from the reservoir as a mist by operation of the aerosol generator.
 2. The nebulizer of claim 1 wherein the medicine vial assembly further comprises a collar having a tab and the reservoir assembly comprises a detent that interlocks with the tab to hold together the vial assembly and the reservoir assembly.
 3. The nebulizer of claim 2 wherein the tab interlocks with the detent to prevent uncoupling and holds the vial assembly and the reservoir assembly together.
 4. The nebulizer of claim 1 wherein the medicine vial assembly further comprises a collar having a plurality of tabs and the reservoir assembly comprises a plurality of detents that interlock within the tabs to hold together the vial assembly and the reservoir assembly.
 5. The nebulizer of claim 4 wherein the tabs interlock with the detents to hold the vial assembly and the reservoir assembly in mutual assembly with each other.
 6. The nebulizer of claim 5 wherein the tabs interlock with the detents to prevent disassembly of the vial assembly and the reservoir assembly once they are assembled together.
 7. The nebulizer of claim 1 wherein the reservoir assembly comprises a reservoir and a cannula in fluid communication with the reservoir and wherein the cannula engages in fluid communication with the medicine vial assembly.
 8. The nebulizer of claim 7 wherein the reservoir assembly further comprises a channel connecting the cannula with the reservoir in fluid communication.
 9. The nebulizer of claim 7 further comprising a valve that opens to permit fluid to move from the medicine vial into the reservoir and closes to prevent reverse flow of fluid from the reservoir to the medicine vial.
 10. The nebulizer of claim 1 wherein the medicine vial assembly comprises a moveable portion that may be moved by advancement of the plunger.
 11. The nebulizer of claim 2 wherein the medicine vial assembly comprises a vial containing medicine fluid, an opening of the vial and a movable stopper situated within the opening of the vial, wherein the plunger acts on the movable stopper when the actuator button is pressed thereby moving fluid out of the medicine vial.
 12. The nebulizer of claim 10 wherein the reservoir assembly comprises a reservoir and a cannula in fluid communication with the reservoir and wherein the cannula is received within the medicine vial assembly.
 13. The nebulizer of claim 12 wherein the cannula is received within the medicine vial and wherein movement of the plunger causes fluid to move from the medicine vial through the cannula into the reservoir.
 14. The nebulizer of claim 1 wherein the reservoir assembly permanently engages the medicine vial assembly
 15. A nebulizer comprising a container containing fluid, a reservoir in fluid communication with the container, an aerosol generator situated to eject fluid from the reservoir as an aerosol, a dose selection mechanism permitting a user to select an amount of fluid to be moved from the container into the reservoir, and an actuator moveably mounted on the nebulizer wherein operation of the actuator by a user causes the selected amount of fluid to be moved from the container into the reservoir.
 16. The nebulizer of claim 15 further comprising a plunger moveably mounted in the nebulizer and wherein operation of the actuator moves the plunger to act upon the container and wherein the dose selection mechanism sets the distance of movement of the plunger.
 17. The nebulizer of claim 15 further comprising a plunger moveably mounted in the nebulizer and wherein the distance of movement of the plunger is set by operation of the dose selection mechanism and the movement of the plunger is effected by operation of the actuator.
 18. The nebulizer of claim 17 wherein the container comprises an opening and a moveable seal friction fit within the opening and wherein the plunger is positioned to act upon the moveable seal when the actuator is operated.
 19. The nebulizer of claim 18 wherein the moveable seal is moved through the container by action of the plunger upon it.
 20. The nebulizer of claim 19 wherein the container defines a longitudinal axis therein and the stopper is moved through the container in a direction parallel to the longitudinal axis.
 21. The nebulizer of claim 21 wherein the actuator is moveably mounted to move in a direction substantially parallel to the longitudinal axis of the container.
 22. The nebulizer of claim 15 wherein the dose selection mechanism comprises a knob that is rotatably mounted on the nebulizer, and the degree of rotation sets the distance of movement of the plunger and a visual indicator acted upon by rotation of the knob to provide a visual indication of the amount of fluid displaced by a selected distance of movement of the plunger.
 23. The nebulizer of claim 22 wherein the visual indicator comprises a numerical display and numbers from 0 to a predetermined maximum and the numbers each correspond to the amount of fluid that will be displaced by a selected distance of movement of the plunger.
 24. The nebulizer of claim 22 wherein the knob is rotatably mounted to rotate in a plane substantially perpendicular to the longitudinal axis of the container
 25. The nebulizer of claim 22 wherein the knob is rotatably mounted to rotate circumferentially with respect to the longitudinal axis of the container.
 26. The nebulizer of claim 20 further comprising a retainer that releasably captures the actuator when the actuator is fully moved a distance from an initial position to a predetermined actuation position.
 27. The nebulizer of claim 26 further comprising a release mechanism operable to release the retainer to allow the actuator to return to an initial position from a predetermined actuation position.
 28. The nebulizer of claim 27 further comprising a reset mechanism that resets the visual indicator from a selected fluid amount indication to a zero indication.
 29. The nebulizer of claim 28 further wherein the release mechanism and the reset mechanism are linked together such that operation of the release mechanism causes operation of the reset mechanism to reset the visual indictor.
 30. The nebulizer of claim 23 wherein the dose selection mechanism comprises an electronically operable numerical display and electronic circuitry responsive to rotation of the knob.
 31. The nebulizer of claim 29 wherein the dose selection mechanism comprises an electronically operable numerical display and an electronic circuitry responsive to rotation of the knob such that rotation of the knob to select a particular distance of movement of the plunger causes the numerical display to display a value corresponding to the amount of fluid that will be displaced by a selected distance of movement of the plunger.
 32. The nebulizer of claim 31 wherein the electronic circuitry is responsive to operation of the release mechanism such that operation of the release mechanism causes the numerical display to be reset to an initial numerical value.
 33. A method of delivering a nebulized fluid for inhalation, comprising: providing an aerosol generator; providing a container containing a fluid to be nebulized; providing a reservoir in fluid communication with the container and with the aerosol generator; providing a moveable member positioned to act upon the container in a manner to displace fluid therefrom providing a screw assembly operable through a range of operating positions situated to act upon the moveable member to selectively limit the distance of movement of the moveable member; selecting a distance of movement of the of the moveable member by operating the screw assembly to a selected operating position; moving the moveable member through the selected distance of movement to displace fluid from the container into the reservoir; and operating the aerosol generator to eject fluid from the reservoir as a nebulized fluid for inhalation.
 34. The method of claim 33 wherein the container defines a longitudinal axis and the moveable member is moveable in a direction substantially parallel to the longitudinal axis.
 35. The method of claim 34 further providing a visual indicator linked to the screw assembly such that operation of the screw assembly causes a visual indication corresponding to the distance of movement the moveable member can move for a selected position of operation of the screw assembly.
 36. The method of claim 35 wherein the visual indicator is one of a liquid crystal display and a light emitting diode and the visual indicator is linked to the screw assembly by an electronic circuitry such that operation of the screw assembly causes the visual indicator to display one of a range of numerical values that corresponds to the distance of movement of the moveable member for a selected position of operation of the screw assembly.
 37. The method of claim 35 wherein each of the numerical values corresponds to a precalculated fluid volume to be displaced from the container by movement of the moveable member a distance based on a selected position of operation of the screw assembly.
 38. The method of claim 35 wherein the step of selecting a distance of movement of the of the moveable member by operating the screw assembly to a selected operating position is carried out by selecting a position of operation of the screw assembly based on a displayed numerical value.
 39. The method of claim 33, further providing a selection knob linked to the screw assembly and a visual indicator linked to the selection knob such that operation of the selection knob causes operation of the screw assembly and operation of the visual indicator.
 40. A nebulizer comprising: a container containing fluid, a reservoir in fluid communication with the container, an aerosol generator situated to eject fluid from the reservoir as an aerosol, a dose selection mechanism permitting a user to select an amount of fluid to be moved from the container into the reservoir, and an actuator moveably mounted on the nebulizer wherein operation of the actuator by a user causes the selected amount of fluid to be moved from the container into the reservoir.
 41. The nebulizer of claim 40 further comprising a plunger moveably mounted in the nebulizer and wherein the distance of movement of the plunger is set by operation of the dose selection mechanism and the movement of the plunger is effected by operation of the actuator.
 42. The nebulizer of claim 40 wherein the container defines a longitudinal axis therein and the stopper is moved through the container in a direction parallel to the longitudinal axis.
 43. The nebulizer of claim 40 wherein the actuator is moveably mounted to move in a direction substantially parallel to the longitudinal axis of the container.
 44. The nebulizer of claim 40 wherein the dose selection mechanism comprises a knob that is rotatably mounted on the nebulizer, and the degree of rotation sets the distance of movement of the plunger and a visual indicator acted upon by rotation of the knob to provide a visual indication of the amount of fluid displaced by a selected distance of movement of the plunger.
 45. The nebulizer of claim 40 wherein the visual indicator comprises a numerical display and numbers from 0 to a predetermined maximum and the numbers each correspond to the amount of fluid that will be displaced by a selected distance of movement of the plunger.
 46. The nebulizer of claim 40 wherein the knob is rotatably mounted to rotate in a plane substantially perpendicular to the longitudinal axis of the container.
 47. The nebulizer of claim 40 wherein the knob is rotatably mounted to rotate circumferentially with respect to the longitudinal axis of the container.
 48. The nebulizer of claim 40 further comprising a retainer that releasably captures the actuator when the actuator is fully moved a distance from an initial position to a predetermined actuation position.
 49. The nebulizer of claim 48 further comprising a release mechanism operable to release the retainer to allow the actuator to return to an initial position from a predetermined actuation position.
 50. The nebulizer of claim 49 further comprising a reset mechanism that resets the visual indicator from a selected fluid amount indication to a zero indication.
 51. The nebulizer of claim 50 further wherein the release mechanism and the reset mechanism are linked together such that operation of the release mechanism causes operation of the reset mechanism to reset the visual indictor.
 52. A method of delivering a nebulized fluid for inhalation, comprising the steps of: providing an aerosol generator, a container containing a fluid to be nebulized, a reservoir in fluid communication with the container and with the aerosol generator, a moveable member positioned to act upon the container in a manner to eject fluid therefrom, and a linkage mechanism coupled to the moveable member to selectively control the distance of movement of the moveable member, selecting a distance of travel of the of the moveable member, moving the moveable member to eject fluid from the container into the reservoir, operating the aerosol generator to eject fluid from the reservoir as a nebulized fluid for inhalation.
 53. A nebulizer comprising a titration mechanism, a dispensing mechanism aerosol generator; the titration mechanism comprises: a housing configured to receive a medicine vial defining a central axis therein, a plunger movably mounted within the housing to travel to and fro substantially parallel to the central axis of a vial when such a vial is received within the housing, an actuator button configured to move the plunger when said actuator button is pressed by a user; a titration control mechanism operable to selectively control the distance of travel of the plunger when the actuator button is pressed, and wherein the dispensing mechanism comprises: a cannula, a reservoir comprising a lumen defined by a wall, and a delivery tube in fluid communication between the cannula and the reservoir lumen wherein the cannula is configured to engage in fluid communication with a medicine vial and wherein fluid can be moved from a medicine vial through the cannula and through the delivery tube to the reservoir; and wherein the aerosol generator is mounted within the lumen wall of the reservoir such that when the aerosol generator is operated, fluid within the reservoir is moved from the reservoir and released therefrom as a mist.
 54. The nebulizer of claim 53, wherein the titration control mechanism comprises a numerical indicator capable of providing a numerical value corresponding the distance of travel of the plunger that the titration control mechanism will provide for a selected numerical value provided by the numerical indicator.
 55. The nebulizer of claim 54, wherein the numerical indicator is capable of providing a plurality of numerical values corresponding to discrete distances of travel of the plunger that the titration control mechanism will provide for a selected numerical value provided by the numerical indicator.
 56. The nebulizer of claim 54, wherein the plurality of numerical values of the numerical indicator are indexed to discrete volumetric amounts corresponding to the volume of fluid displaced by a predetermined distance of travel of the plunger when a vial containing fluid is received within the titration control mechanism housing.
 57. The nebulizer of claim 54, wherein the plurality of numerical values of the numerical indicator are indexed to discrete volumetric amounts corresponding to the volume of fluid displaced by a predetermined distance of travel of the plunger when a vial containing fluid is received within the titration control mechanism housing.
 58. The nebulizer of claim 53 wherein the titration control mechanism further comprises a screw assembly that allows the plunger to travel a selected distance by a fixed distance of movement of the actuator button.
 59. The nebulizer of claim 58, wherein the titration control mechanism comprises a numerical indicator capable of providing a numerical value corresponding the distance of travel of the plunger that the titration control mechanism will provide for a selected numerical value provided by the numerical indicator.
 60. A nebulizer comprising: a titration mechanism; a vial assembly comprising a vial; and an aerosol generator; wherein the vial has a ratio of inside diameter to vial length of between about 1:3.5 to about 1:4.5.
 61. The nebulizer of claim 60 wherein the ratio is about 1:3.7 to about 1:4.2.
 62. The nebulizer of claim 60 wherein the ratio is about 1:3.8 to about 1:4.0.
 63. The nebulizer of claim 60 wherein the ratio is about 1:3.9.
 64. A nebulizer comprising: a titration mechanism; a vial assembly comprising a vial; and an aerosol generator; wherein the vial has a ratio of inside diameter to vial length of between about 1:3.0 and about 1:3.8.
 65. The nebulizer of claim 64 wherein the ratio is between about 1:3.2 to about 1:3.6.
 66. The nebulizer of claim 64 wherein the ratio is between about 1:3.3 to about 1:3.5.
 67. The nebulizer of claim 64 wherein the ratio is between about 1:3.4 to about 1:3.6.
 68. The nebulizer of claim 64 wherein the diameter of the vial is about 12 mm and the effective length of the vial is about 38 mm.
 69. The nebulizer of claim 64 wherein the diameter of the vial is about 12.0 mm and the effective length of the vial is about 37.7 mm.
 70. A nebulizer comprising: a titration mechanism; a vial assembly; and an aerosol generator, the aerosol generator comprising an aerosol element comprising palladium.
 71. The nebulizer of claim 70, wherein the aerosol element comprises between about 50% and about 100% palladium.
 72. The nebulizer of claim 70, wherein the aerosol element comprises palladium and nickel.
 73. The nebulizer of claim 70, wherein the aerosol element consists essentially of palladium.
 74. The nebulizer of claim 70, wherein the aerosol element consists of palladium.
 75. A nebulizer comprising: a titration mechanism; a vial mechanism; an aerosol generator; and a switch responsive to inhalation by a user.
 76. The nebulizer of claim 75 wherein the switch comprises a sensor to sense a pressure drop.
 77. The nebulizer of claim 76, further comprising a mouthpiece and wherein the switch comprises a sensor to sense a pressure drop in the mouthpiece.
 78. The nebulizer of claim 75, further comprising a controller, wherein the controller controls operation of the aerosol generator based on the switch responding to inhalation.
 79. The nebulizer of claim 78, wherein the controller comprises a timing element.
 80. The nebulizer of claim 79, wherein the controller is configured to operate the aerosol generator upon an inhalation and to cease operation of the aerosol generator after a predetermined time.
 81. The nebulizer of claim 80, wherein the predetermined time is between about 3 seconds and about 5 seconds.
 82. The nebulizer of claim 81, wherein the predetermined time is between about 3.5 seconds and about 4.5 seconds.
 83. The nebulizer of claim 81, wherein the predetermined time is about 4 seconds.
 84. A nebulizer comprising: a titration mechanism; a vial mechanism; an aerosol generator for generating aerosol from a liquid; and a switch responsive to the amount of liquid available to the aerosol generator.
 85. The nebulizer of claim 84, wherein the aerosol generator comprises a comprises a vibratory aerosolization element and a vibratory element, and wherein the switch senses a change in amplitude of vibration based on a change in the amount of liquid in contact with the aerosolization element.
 86. The nebulizer of claim 85, wherein the switch comprises a sensor configured to sense a change in amplitude of vibration of the aerosolization element.
 87. The nebulizer of claim 86, further comprising a controller, the controller configured to control operation of the aerosolization element, and wherein the switch comprises the sensor and the control of the controller over the operation of the aerosolization element.
 88. The nebulizer of claim 84, wherein the switch is configured to respond to depletion of liquid in contact with the aerosol generator.
 89. The nebulizer of claim 88, wherein the switch causes the aerosol generator to cease operation at a predetermined level of liquid depletion.
 90. The nebulizer of claim 89, further comprising a controller to control the operation of the aerosol in response to the switch.
 91. The nebulizer of claim 84, wherein the switch is configured to respond to the addition of liquid in contact with the aerosol generator.
 92. A nebulizer comprising: a titration mechanism; a vial mechanism; an aerosol generator for generating aerosol from a liquid; a a first switch configured to respond to the presence of a predetermined minimum amount of liquid available to the aerosol generator; and a second switch configured to respond to the absence of a predetermined minimum amount of liquid available to the aerosol generator.
 93. The nebulizer of claim 92, wherein the aerosol generator comprises a vibratory aerosolization element and a vibratory element, and wherein the first switch and the second switch each comprise a sensor that senses a change in amplitude of vibration based on a change in the amount of liquid in contact with the aerosolization element.
 94. The nebulizer of claim 93, wherein the first of the first switch is configured to detect a change in amplitude corresponding to the aerosolization element being first state with an absence of a predetermined amount of liquid in contact with it and the second state with a presence of a predetermined amount of liquid in contact with it, and the second switch is configured to detect a change in amplitude corresponding to the aerosolization element being first in a state with a presence of a predetermined amount of liquid in contact with it and a second state with an absence of a predetermined amount of liquid in contact with it.
 95. A nebulizer comprising: a titration mechanism; a vial mechanism; an aerosol generator; and at least one light, the light providing information to a user on at least one of the operability of the nebulizer and the state of operation of the nebulizer.
 96. A nebulizer comprising: a titration mechanism; a vial mechanism comprising a vial containing insulin; and an aerosol generator.
 97. The nebulizer of claim 96, wherein the aerosol generator further comprises a vibratory apertured aerosolization element and a vibratory element configured to vibrate the aerosolizatin element.
 98. The nebulizer of claim 97, further comprising a reservoir, wherein the aerosolization element comprises a first face and a second face, and wherein the first face faces into the reservoir.
 99. The nebulizer of claim 98, wherein the first face is concave.
 100. The nebulizer of claim 99, wherein the second face is convex.
 101. The nebulizer of claim 97, wherein the apertures are tapered to narrow from the first face toward the second face.
 102. A nebulizer comprising: a titration mechanism; a vial mechanism; an aerosol generator; and a controller to control operation of the aerosol generator.
 103. The nebulizer of claim 102, wherein the controller is configured to provide a fixed length of time for operation of the aerosol generator.
 104. The nebulizer of claim 103, wherein the fixed time is between about 3 seconds and about 5 seconds.
 105. The nebulizer of claim 104, wherein the fixed time is approximately 4 seconds.
 106. A method of nebulizing a liquid, comprising: providing a nebulizer comprising a titration mechanism, a vial mechanism and an aerosol generator; instructing a user to inhale for B seconds; and operating the aerosol generator to produce aerosol from the liquid for A seconds, wherein A and B represent real numbers.
 107. The method of claim 106, wherein A is less than B.
 108. The method of claim 107, wherein A=B−N.
 109. The method of claim 108, wherein N=1.
 110. The method of claim 109, wherein B is approximately 5 seconds.
 111. The method of claim 110, wherein the liquid is a drug for systemic administration.
 112. The method of claim 111, wherein the liquid is insulin.
 113. The method of claim 107, wherein the liquid is insulin.
 114. The method of claim 108, wherein the liquid is insulin.
 115. The method of claim 110, wherein the liquid is insulin.
 116. A method of providing aerosolized insulin to a user, comprising: providing a nebulizer comprising a titration mechanism, a vial mechanism, an aerosol generator, and a reservoir; operating the titration mechanism to select a dose of insulin for inhalation; actuating the titration mechanism to displace the selected dose of insulin from the vial mechanism and into the reservoir; commencing inhalation through the nebulizer; operating the aerosol generator; ceasing operation of the aerosol generator while inhalation continues; ceasing inhalation after cessation of operation of the aerosol generator.
 117. A method of aerosolizing a liquid, comprising, providing a nebulizer comprising an aerosol generator; providing a titration mechanism in the nebulizer, the titration mechanism comprising a dosing mechanism, a screw mechanism, an actuator and a plunger, the plunger movable along a longitudinal axis within the nebulizer, the actuator movable a fixed distance X along the axis defined by the plunger and the dosing mechanism rotatable in a plane substantially perpendicular to the longitudinal axis; providing a vial mechanism comprising a vial, the vial having a longitudinal axis and a movable seal movable along the longitudinal axis; inserting the vial mechanism into the nebulizer such that the longitudinal axis of the vial is substantially parallel to the longitudinal axis of the plunger; rotating the dosing mechanism to select a dose, operating the screw mechanism, by rotating the dosing mechanism, to set a variable distance Y of travel of the plunger corresponding to a selected dose without imparting longitudinal travel of the plunger; moving the actuator longitudinally the fixed distance X to move the plunger longitudinally the selected variable distance Y; moving the movable stopper the variable distance Y by movement of the plunger the selected variable distance Y; displacing a volume of liquid, corresponding to the selected dose, from the vial to contact the aerosol generator; operating the aerosol generator to aerosolize the liquid.
 118. The method of claim 117, wherein the aerosol generator comprises an aerosolization element having a first face, a second face and a plurality of apertures therethrough and wherein operating the aerosol generator comprises vibrating the aerosolization element.
 119. The method of claim 117, further comprising inserting a reservoir into the nebulizer, and wherein the liquid is displaced from the vial into the reservoir.
 120. The method of claim 117, wherein the nebulizer further comprises a reservoir, and wherein the liquid is displaced from the vial into the reservoir.
 121. A nebulizer comprising: a titration mechanism comprising a longitudinally moveable plunger, the movement thereof defining a longitudinal axis, a longitudinally moveable actuator to move the plunger, the movement of the actuator defining a longitudinal axis, and a screw mechanism to set the distance of travel of the plunger; a rotatably mounted dosing mechanism, the rotation thereof defining an axis of rotation, a vial mechanism comprising a vial defining a longitudinal access and a moveable seal moveable along the longitudinal access of the vial; an aerosol generator; and a controller to control operation of the aerosol generator, wherein the longitudinal axis of the plunger and the longitudinal axis of the actuator are parallel, and wherein the dosing mechanism is rotatable in a plane substantially perpendicular to the longitudinal axes.
 122. The nebulizer of claim 121, wherein the longitudinal axis of the plunger, the longitudinal axis of the actuator and the axis of rotation of the dosing mechanism are substantially coaxial.
 123. The nebulizer of claim 122, wherein the axes are coaxial.
 124. The nebulizer of claim 122 wherein the longitudinal axis of the vial is coaxial with the axis of rotation of the dosing mechanism.
 125. A method of nebulizing a liquid comprising: providing a titration mechanism comprising a longitudinally moveable plunger, the movement thereof defining a longitudinal axis, a longitudinally moveable actuator to move the plunger, the movement of the actuator defining a longitudinal axis, and a screw mechanism to set the distance of travel of the plunger; providing a rotatably mounted dosing mechanism, the rotation thereof defining an axis of rotation, providing a vial mechanism comprising a vial defining a longitudinal access and a moveable seal moveable along the longitudinal access of the vial; providing an aerosol generator; providing a controller to control operation of the aerosol generator, placing the vial-mechanism within the nebulizer such that the longitudinal axis of the vial is substantially coaxial with the axis of rotation of the dosing mechanism; rotating the dosing mechanism to select a dose; moving the actuator to move the plunger such that fluid is dispensed from the vial; operating the aerosol generator to nebulize the liquid. 